In previous annual reports, the first development of anti- retroviral drugs belonging to the dideoxynucleoside family was outlined. One such drug (AZT) has now achieved prescription status. Two others, ddC and ddA, have continued in our development effort. The goal is to find drugs which, alone or in combination, have a better therapeutic index than AZT alone. In a Phase 1 dose- seeking trial, we administered 5 dose regimens of 2',3' dideoxycytidine (ddC), a cytidine analogue with potent in vitro activity against human immunodeficiency virus (HIV) which had never previously been given to man, to 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). ddC was administered intravenously for 2 weeks and then orally for 4 or more weeks. ddC was well absorbed from the gut and crossed the bloodbrain barrier in these patients. Ten of the 15 patients who received 0.03 mg/kg to 0.09 mg/kg ddC every 4 hrs had increases in their absolute number of T4+ T cells at week 2 (p less than 0.05); in many of the patients, however, these rises were not sustained. Eleven of 13 evaluable patients had a fall in their serum HIV p24 antigen by week 2 of therapy (P less than 0.01); in a few patients, the p24 antigen subsequently role to baseline while in most the decline was sustained. Dose-related toxicities included a transient symptom complex of cutaneous eruptions, fever, and mouth sores; thrombocytopenia; and neutropenia. A late toxicity appearing after 6 to 14 weeks on ddC was reversible painful peripheral neuropathy. These results suggest that ddC has activity against HIV in vivo and has a different toxicity profile than 3'-azido-2',3'-dideoxythymidine (AZT). Based on these different toxicity profiles, we subsequently administered a regimen of AZT (200 mg orally every 4 hrs for 7 days) alternating with ddC (0.03 mg/kg every 4 hrs for 7 days) as a feasibility study. The regimen appears active and has less toxicity than either agent alone.